Anticonvulsant

Anticonvulsants (also commonly known as antiepileptic drugs or as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epilepticseizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder[1] and borderline personality disorder,[2] since many seem to act as mood stabilizers, and for the treatment of neuropathic pain.[3] Anticonvulsants suppress the rapid and excessive firing of neurons during seizures.[4] Anticonvulsants also prevent the spread of the seizure within the brain.[5] Some investigators have observed that anticonvulsants themselves may cause reduced IQ in children.[6] However these adverse effects must be balanced against the significant risk epileptic seizures pose to children and the distinct possibility of death and devastating neurological sequelae secondary to seizures. Anticonvulsants are more accurately called antiepileptic drugs (abbreviated "AEDs"), and are often referred to as antiseizure drugs because they provide symptomatic treatment only and have not been demonstrated to alter the course of epilepsy.

Conventional antiepileptic drugs may block sodium channels or enhance γ-aminobutyric acid (GABA) function. Several antiepileptic drugs have multiple or uncertain mechanisms of action.[7] Next to the voltage-gated sodium channels and components of the GABA system, their targets include GABAA receptors, the GAT-1 GABA transporter, and GABA transaminase.[8] Additional targets include voltage-gated calcium channels, SV2A, and α2δ.[9][10] By blocking sodium or calcium channels, antiepileptic drugs reduce the release of excitatory glutamate, whose release is considered to be elevated in epilepsy, but also that of GABA.[11] This is probably a side effect or even the actual mechanism of action for some antiepileptic drugs, since GABA can itself, directly or indirectly, act proconvulsively.[11] Another potential target of antiepileptic drugs is the peroxisome proliferator-activated receptor alpha.[12][13][14][15][16][17][18] The drug class was the 5th-best-selling in the US in 2007.[19]

Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy.[20] That is, they either prevent the development of epilepsy or can halt or reverse the progression of epilepsy. However, no drug has been shown in human trials to prevent epileptogenesis (the development of epilepsy in an individual at risk, such as after a head injury).[21]

The usual method of achieving approval for a drug is to show it is effective when compared against placebo, or that it is more effective than an existing drug. In monotherapy (where only one drug is taken) it is considered unethical by most to conduct a trial with placebo on a new drug of uncertain efficacy. This is because untreated epilepsy leaves the patient at significant risk of death. Therefore, almost all new epilepsy drugs are initially approved only as adjunctive (add-on) therapies. Patients whose epilepsy is currently uncontrolled by their medication (i.e., it is refractory to treatment) are selected to see if supplementing the medication with the new drug leads to an improvement in seizure control. Any reduction in the frequency of seizures is compared against a placebo.[21] The lack of superiority over existing treatment, combined with lacking placebo-controlled trials, means that few modern drugs have earned FDA approval as initial monotherapy. In contrast, Europe only requires equivalence to existing treatments, and has approved many more. Despite their lack of FDA approval, the American Academy of Neurology and the American Epilepsy Society still recommend a number of these new drugs as initial monotherapy.[21]

Phenobarbital was the main anticonvulsant from 1912 until the development of phenytoin in 1938. Today, phenobarbital is rarely used to treat epilepsy in new patients since there are other effective drugs that are less sedating. Phenobarbital sodium injection can be used to stop acute convulsions or status epilepticus, but a benzodiazepine such as lorazepam, diazepam or midazolam is usually tried first. Other barbiturates only have an anticonvulsant effect at anaesthetic doses.

The benzodiazepines are a class of drugs with hypnotic, anxiolytic, anticonvulsive, amnestic and muscle relaxant properties. Benzodiazepines act as a central nervous system depressant. The relative strength of each of these properties in any given benzodiazepine varies greatly and influences the indications for which it is prescribed. Long-term use can be problematic due to the development of tolerance to the anticonvulsant effects and dependency.[24][25][26][27] Of the many drugs in this class, only a few are used to treat epilepsy:

Nitrazepam, temazepam, and especially nimetazepam are powerful anticonvulsant agents, however their use is rare due to an increased incidence of side effects and strong sedative and motor-impairing properties.

The first anticonvulsant was bromide, suggested in 1857 by Charles Locock who used it to treat women with "hysterical epilepsy" (probably catamenial epilepsy). Bromides are effective against epilepsy, and also cause impotence, which is not related to its anti-epileptic effects. Bromide also suffered from the way it affected behaviour, introducing the idea of the 'epileptic personality' which was actually a result of medication. Phenobarbital was first used in 1912 for both its sedative and antiepileptic properties. By the 1930s, the development of animal models in epilepsy research led to the development of phenytoin by Tracy Putnam and H. Houston Merritt, which had the distinct advantage of treating epileptic seizures with less sedation.[33] By the 1970s, a National Institutes of Health initiative, the Anticonvulsant Screening Program, headed by J. Kiffin Penry, served as a mechanism for drawing the interest and abilities of pharmaceutical companies in the development of new anticonvulsant medications.

The following table lists anticonvulsant drugs together with the date their marketing was approved in the US, UK and France. Data for the UK and France are incomplete. In recent years, the European Medicines Agency has approved drugs throughout the European Union. Some of the drugs are no longer marketed.

During pregnancy, the metabolism of several anticonvulsants is affected. There may be an increase in the clearance and resultant decrease in the blood concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative.[72] Therefore, these drugs should be monitored during use in pregnancy.[72]

Many of the common used medications, such as valproate, phenytoin, carbamazepine, phenobarbitol, gabapentin have been reported to cause increased risk of birth defects.[73] Among anticonvulsants, levetiracetam and lamotrigine seem to carry the lowest risk of causing birth defects. The risk of untreated epilepsy is believed to be greater than the risk of adverse effects caused by these medications, necessitating continuation of antiepileptic treatment.

Regarding breastfeeding, some anticonvulsants probably pass into breast milk in clinically significant amounts, including primidone and levetiracetam.[72] On the other hand, valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts.[72]

^American Psychiatric Association, and American Psychiatric Association. Work Group on Borderline Personality Disorder. Practice guideline for the treatment of patients with borderline personality disorder. American Psychiatric Pub, 2001.